Substituted benzothiazoles as orexin antagonists

ABSTRACT

The present invention is concerned with novel sulfonamides of formula I 
                         
wherein R 1 , R 2 , Ar, Hetaryl, m and n are as described in the description and claims. The compounds are orexin receptor antagonists, useful in the treatment of disorders, in which orexin pathways are involved.

PRIORITY TO RELATED APPLICATION(S)

This application is a division of U.S. application Ser. No. 12/506,302,filed Jul. 21, 2009, now pending; which claims the benefit of EuropeanPatent Application No. 08161316.8, filed Jul. 29, 2008. The entirecontents of the above-identified applications are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

Orexins (hypocretins), a family of hypothalamic neuropeptides, play animportant role in modulating feeding behavior, energy homeostasis andthe sleep-wake cycle (Siegel, Annu. Rev. Psychol., 55, 125-148, 2004).The orexin-A/hypocretin1 (OX-A, 33 amino acids) and orexin-B/hypocretin2(OX-B, 28 amino acids) are derived from the same precursor byproteolytic processing of 130 amino acids prepro-orexin (de Lecea etal., Proc Natl Acad Sci USA, 95, 322-327, 1998; Sakurai T. et al., Cell,92, 573-585, 1998). The orexin levels show a diurnal variation beinghighest during the active cycle. Two receptor subtypes termed orexin-1receptor (OX₁R) and orexin-2 receptor (OX₂R) have been identified. Thecharacterization of both receptors in binding and functional assaysdemonstrated that OX₂R is a non-selective receptor for both OX-A and -B,whereas OX₁R is selective for OX-A, conversely OX-A is a non-selectiveneuropeptide and binds with similar affinities to OX₁R and OX₂R, whileOX-B is selective and has a higher affinity for OX2R (Sakurai T. et al.,Cell, 92, 573-585, 1998). Both receptors belong to the class A family ofG-protein-coupled receptors (GPCRs) that couple via G_(q/11) to theactivation of phospholipase C leading to phosphoinositide (PI)hydrolysis and elevation of intracellular Ca²⁺ levels. However, it hasbeen shown that OX2R could also couple via G_(i/o) to cAMP pathway(Sakurai, Regulatory Peptides, 126, 3-10, 2005). Northern blot analysisof adult rat tissues showed that the prepro-orexin mRNA is detectedexclusively in the brain (except for a small amount in the testis) andthat the OX₁R and OX₂R transcripts are also exclusively detected in thebrain (Sakurai T. et al., Cell, 92, 573-585, 1998). Similar results wereobtained using human multiple tissue Northern blot. Distribution studiesin rat brain using in situ hybridization and immunohistochemistry haveshown that orexin neurons are found only in the lateral hypothalamicarea with their projections to the entire CNS (Peyron et al., JNeurosci, 18, 9996-10015, 1998; Nambu et al., Brain Res., 827, 243-60,1999). In addition, both OX₁ and OX₂ receptors are present in brainregions important for the regulation of sleep/wakefulness.

A disrupted orexin system is suggested to be the cause of narcolepsybased on following lines of evidence: (a) Prepro-orexin knockout micepossessed a phenotype with characteristics remarkably similar tonarcolepsy (Chemelli et al., Cell, 98, 437-451, 1999), (b) a mutation(canarc-1), which disrupts the gene encoding OX₂R, was found to beresponsible for canine narcolepsy (Lin et al., Cell, 98, 365-376, 1999),(c) lack of OX-A and OX-B was observed in human narcoleptic patients(Nishino et al., Lancet, 355, 39-40, 2000; Peyron et al., NatureMedicine, 6, 991-997, 2000), (d) it has been shown that Modafinil, ananti-narcoleptic drug with unknown mechanism of action, activates orexinneurons (Mignot et al., Sleep, 11, 1012-1020, 1997; Chemelli et al.,Cell, 98, 437-451, 1999). The intracerebroventricular (icy)administration of OX-A dose-dependently increases wakefulness in rat andalso reduces total REM sleep by 84% (Piper et al., Eur. J. Neuroscience,12, 726-730, 2000). Taken together, these observations are consistentwith a crucial role of the orexin system in the modulation of sleep/wakecycle.

Orexin plays an important role in stress and anxiety via its interactionwith the orticotrophin-releasing factor (CRF) system in hypothalamus(Sakamoto et al., Regul Pept., 118, 183-91, 2004). The icv injection ofOX-A induces grooming (stress-response) which is blocked in part by aCRF antagonist (Ida et al., Biochem. Biophys. Res. Comm., 270, 318-323,2000). OX₂R is highly expressed in adrenal medulla, whereas OX₁R is highin adrenal cortex. Both OX-A and OX-B stimulate corticosterone releasein plasma and induce c-Fos in paraventricular nucleus (PVN) in thehypothalamus (Kuru et al., Neuroreport, 11, 1977-1980, 2000).Furthermore, orexin neurons projecting to CRF neurons express mainly theOX₂R (Winsky-Sommerer et al., J. Neuroscience, 24, 11439-11448, 2004).Therefore, OX2R stimulation activates the hypothalamo-pituitary-adrenal(HPA) axis. Interestingly, in this context, the orexin A-inducedincreases in plasma ACTH has been reported to be attenuated by aselective antagonist toOX-2R(N-{(1S)-1-(6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl)carbonyl}-2,2-dimethylpropyl)-N-{4-pyridinylmethyl}amine(Chang et al., Neurosci Res., 21 Dec. 2006). A recent preclinical report(Suzuki et al., Brain Research, 1044, 116-121, 2005) has suggested ananxiogenic effect of OX-A. The icv injection of OX-A caused ananxiety-like behavior in mice. Effects were similar to those oforticotrophin-releasing factor (CRF) that was tested at the same timefor comparison. A recent study has also demonstrated the presence offunctional OX1 and OX2 receptors in human adipose tissue and their rolesin adipose tissue metabolism and adipogenesis (Digby et al., J.Endocrinol., 191, 129-36, 2006).

In summary, considering the very diverse functions played by orexinsystem in arousal, sleep/wakefulness, appetite regulation and theirroles in anxiety and stress response, etc., one expects that the drugs(or compounds) targeting orexin system will have beneficial therapeuticeffects for the treatments of diseases like sleep disorders includingsleep apnea, narcolepsy, insomnia, parasomnia, jet lag syndrome,circadian rhythms disorder, restless leg syndrome, psychiatric,neurological and neurodegenerative disorders including anxiety,depression, manic depression, obsessive compulsive disorders, affectiveneurosis, depressive neurosis, anxiety neurosis, mood disorder,delirium, panic-attack disorder, posttraumatic stress disorders, sexualdysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer'sand Parkinson's diseases, dementia, mental retardation, dyskinesias suchas Huntington's disease and Tourette syndrome, addictions, cravingassociated with drug abuse, seizure disorders, epilepsy, metabolicdiseases such as obesity, diabetes, eating disorders including anorexiaand bulimia, asthma, migraine, pain, neuropathic pain, sleep disordersassociated with psychiatric, neurological and neurodegenerativedisorders, neuropathic pain, enhanced or exaggerated sensitivity to painsuch as hyperalgesia, causalgia, and allodynia, acute pain, burn pain,back pain, complex regional pain syndrome I and II, arthritic pain,post-stroke pain, post-operative pain, neuralgia, pain associated withHIV infection, post-chemotherapy pain, irritable bowel syndrome andother diseases related to general orexin system dysfunction.

Numerous documents describe the current knowledge on orexin pathway, forexample the following documents:

Expert Opin. Ther. Patents (2006), 16(5), 631-646

Current Opinion in Drug Discovery & Development, 2006, 9(5), 551-559

J. Neurosci (2000), 20(20), 7760-7765

Neurosci Lett, (2003), 341(3), 256-258

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I

-   wherein-   R¹ is halogen;-   R² is halogen, lower alkyl, lower alkoxy, lower alkyl substituted by    halogen, lower alkoxy substituted by halogen or is phenyl;-   Hetaryl is

-   X is O or S;-   Ar is aryl or heteroaryl;-   n is 0, 1 or 2;-   m is 0, 1 or 2;-   or to pharmaceutically suitable acid addition salts, optically pure    enantiomers, racemates or diastereomeric mixtures thereof.

The invention also provides pharmaceutical compositions containingcompounds of the invention and a pharmaceutically acceptable carrier.The invention further provides methods for the manufacture of thecompounds and compositions of the invention.

Compounds of formula I are orexin receptor antagonists. Thus, theinvention also provides methods for the treatment of disorders, in whichorexin pathways are involved like sleep disorders including sleep apnea,narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythmsdisorder, restless leg syndrome, psychiatric, neurological andneurodegenerative disorders including anxiety, depression, manicdepression, obsessive compulsive disorders, affective neurosis,depressive neurosis, anxiety neurosis, mood disorder, delirium,panic-attack disorder, posttraumatic stress disorders, sexualdysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer'sand Parkinson's diseases, dementia, mental retardation, dyskinesias suchas Huntington's disease and Tourette syndrome, addictions, cravingassociated with drug abuse, seizure disorders, epilepsy, metabolicdiseases such as obesity, diabetes, eating disorders including anorexiaand bulimia, asthma, migraine, pain, neuropathic pain, sleep disordersassociated with psychiatric, neurological and neurodegenerativedisorders, neuropathic pain, enhanced or exaggerated sensitivity to painsuch as hyperalgesia, causalgia, and allodynia, acute pain, burn pain,back pain, complex regional pain syndrome I and II, arthritic pain,post-stroke pain, post-operative pain, neuralgia, pain associated withHIV infection, post-chemotherapy pain, irritable bowel syndrome andother diseases related to general orexin system dysfunction.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “lower alkyl” denotes a straight- orbranched-chain hydrocarbon group containing from 1-7 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl andthe like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.

The term “lower alkyl substituted by halogen” denotes a lower alkylgroup as defined above, wherein at least one hydrogen atom is replacedby halogen, for example —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CF₂CHF₂,—CH₂CH₂CF₃, —CH₂CF₂CF₃ and the like. Preferred lower alkyl substitutedby halogen groups are groups having 1-4 carbon atoms.

The term “lower alkoxy” denotes a lower alkyl group as defined above,which is attached via an oxygen atom, for example, methoxy, ethoxy,propoxy, isopropoxy, n-butoxy, i-butoxy, 2-butoxy, t-butoxy and thelike. Preferred alkoxy groups are groups with 1-4 carbon atoms.

The term “lower alkoxy substituted by halogen” denotes a lower alkoxygroup as defined above wherein at least one hydrogen atom is replaced byhalogen. Preferred lower alkoxy substituted by halogen groups are groupshaving 1-4 carbon atoms.

The term “halogen” denotes chlorine, iodine, fluorine and bromine.

The term “aryl” denotes an aromatic mono or bicyclic carbon ring system,for example phenyl or naphthyl, preferably phenyl.

The term “heteroaryl” denotes a five-or six membered aromatic ringsystem, containing one or two heteroatoms, selected from O, S and N, forexample isoxazolyl, oxazolyl, imidazolyl, pyridinyl and the like,preferably isoxazolyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methanesulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

Preferred compounds of formula I are those wherein Hetaryl isbenzoxazol-2-yl,

for example the following examples:

-   {3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-chloro-5-methyl-phenyl)-methanone;-   {(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl)-methanone;-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl)-methanone;-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone;-   (2-chloro-5-methyl-phenyl)-{(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone;    and-   {(S)-3-[(7-fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl)-methanone.

Preferred compounds of formula I-1 as defined above are

-   {3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone;-   {(S)-3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone;-   {(S)-3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;    and-   {(S)-3-[(7-Fluoro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone.

Preferred compounds of formula I are further those wherein Hetaryl isbenzthiazol-2-yl,

for example the following examples:

-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl)-methanone;-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone;-   (2-chloro-5-methyl-phenyl)-{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone;    and-   {(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl)-methanone.

Preferred compounds of formula I-2 as defined above are

-   {(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;-   {(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;    and-   {(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone.

Preferred compounds of formula I are further those wherein Hetaryl isquinoxalin-2-yl,

for example the following examples:

-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl)-methanone;-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl)-methanone;-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone;-   (2-chloro-5-methyl-phenyl)-{(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone;    and-   {(S)-3-[(6-chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl)-methanone.

A preferred compound of formula I-3 as defined above is

-   {(S)-3-[(6-Chloro-quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone.

Preferred compounds as defined above are those, wherein R¹ is Cl or F.Other preferred compounds as defined above are those, wherein n is 1.

Other preferred compounds as defined above are those, wherein R² islower alkyl, lower alkoxy, lower alkoxy substituted by halogen orphenyl, particularly wherein R² is methyl, methoxy,1,1,2,2-tetrafluoro-ethoxy or phenyl.

Preferably, m is 1 or 2. Other preferred compounds as define above arethose, wherein Ar is phenyl or isoxazolyl.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which process comprises

a) reacting a compound of formula

with a compound of formula

or with the corresponding acid chloride thereofto obtain a compound of formula

wherein R′, R², Ar, Hetaryl, m and n are as defined above,and if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

General Experimental Part

The preparation of compounds of formula I of the present invention canbe carried out in sequential or convergent synthetic routes. Synthesesof the compounds of the invention are shown in the following scheme. Theskills required for carrying out the reaction and purification of theresulting products are known to those skilled in the art. Thesubstituents and indices used in the following description of theprocesses have the significance given herein before unless indicated tothe contrary.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. The reactionsequence is not limited to the one displayed in scheme 1, however,depending on the starting materials and their respective reactivity thesequence of reaction steps can be freely altered. Starting materials areeither commercially available or can be prepared by methods analogous tothe methods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

Step a)

Aromatic heterocyclic compounds II are either commercially available orcan be synthesized according to procedures described in literature (forreaction conditions described in literature affecting such reactions seefor example: Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition, Richard C. Larock. JohnWiley & Sons, New York, N.Y. 1999), for instance from their respectiveHET-OH derivatives. Protected amino-methylpyrrolidines III arecommercially available or can be synthesized according to proceduresdescribed in literature. Protected amino-methylpyrrolidines III can bereacted with II in the presence or absence of a solvent and the presenceor the absence of a base. There is no particular restriction on thenature of the solvent to be employed, provided that it has no adverseeffect on the reaction or the reagents involved and that it can dissolvethe reagents, at least to some extent. Examples for suitable solventsinclude dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran(THF) and the like. There is no particular restriction on the nature ofthe base used in this stage, and any base commonly used in this type ofreaction may equally be employed here. Examples of such bases includeNEt₃, DIPEA and the like. The reaction can take place over a wide rangeof temperatures, and the precise reaction temperature is not critical tothe invention. It is convenient to carry out the reaction with heatingfrom ambient temperature to reflux. The time required for the reactionmay also vary widely, depending on many factors, notably the reactiontemperature and the nature of the reagents. However, a period of from0.5 h to several days will usually suffice to yield the protectedintermediate (convenient PG=Boc) which can be subjected to acidiccleavage of the protecting group in the presence of a solvent. There isno particular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or the reagentsinvolved and that it can dissolve the reagents, at least to some extent.Examples for suitable solvents include dichloromethane (DCM), dioxane,tetrahydrofuran (THF) and the like. There is no particular restrictionon the nature of the acid used in this stage, and any acid commonly usedin this type of reaction may equally be employed here. Examples of suchacid include HCl and the like. The reaction can take place over a widerange of temperatures, and the precise reaction temperature is notcritical to the invention. It is convenient to carry out the reactionwith heating from ambient temperature to reflux. The time required forthe reaction may also vary widely, depending on many factors, notablythe reaction temperature and the nature of the reagents. However, aperiod of from 0.5 h to several days will usually suffice to yieldaminomethyl-pyrrolidine derivatives IV.

Step b)

Transformation of intermediate aminomethyl-pyrrolidine derivatives IVwith acids (under coupling conditions with a coupling agent) or acidchlorides V is well know in the art. For analogous examples inliterature refer to Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition, Richard C. Larock. JohnWiley & Sons, New York, N.Y. 1999. However, we find it convenient toreact intermediate aminomethyl-pyrrolidine derivatives IV with acidchlorides in the presence or absence of a base and the presence orabsence of a solvent. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or the reagents involved and that it can dissolve thereagents, at least to some extent. Examples for suitable solventsinclude dichloromethane (DCM), dimethylformamide (DMF), tetrahydrofuran(THF) and the like. There is no particular restriction on the nature ofthe base used in this stage, and any base commonly used in this type ofreaction may equally be employed here. Examples of such bases includepyridine, NEt₃, DIPEA and the like. The reaction can take place over awide range of temperatures, and the precise reaction temperature is notcritical to the invention. It is convenient to carry out the reactionwith heating from ambient temperature to reflux. The time required forthe reaction may also vary widely, depending on many factors, notablythe reaction temperature and the nature of the reagents. However, aperiod of from 0.5 h to several days will usually suffice to yieldaminomethyl-pyrrolidine derivatives I.

The compounds were investigated in accordance with the test givenhereinafter.

Intracellular Ca²⁺ Mobilization Assay

The Chinese Hamster Ovary (dHFr-) mutant cell line stably expressinghuman orexin-1 (hOX1) or human orexin-2 (hOX2) receptors were maintainedin Dulbecco's Modified Eagle Medium (1×) with GlutaMax™1, 4500 mg/LD-Glucose and Sodium Pyruvate (Catalog No. 31966-021, Invitrogen,Carlsbad, Calif.), 5% dialyzed fetal calf serum (Catalog No. 26400-044),100 μg/ml penicillin and 100 μg/ml streptomycin. The cells were seededat 5×10⁴ cells/well in the poly-D-lysine treated, 96-well,black/clear-bottomed plates (Catalog No. BD356640, BD Biosciences, PaloAlto, Calif.). 24 h later, the cells were loaded for 1 h at 37° C. with4 μM Flou-4 acetoxymethyl ester (Catalog No. F-14202, Molecular Probes,Eugene, Oreg.) in FLIPR buffer (1×HBSS, 20 mM HEPES, 2.5 mM Probenecid).Hanks' Balanced Salt Solution (HBSS) (10×) (catalog No. 14065-049) andHEPES (1M) (catalog No. 15630-056) were purchased from Invitrogen,Carlsbad, Calif. Probenecid (250 mM) (catalog No. P8761) was from Sigma,Buchs, Switzerland. The cells were washed five times with FLIPR bufferto remove excess dye and intracellular calcium mobilization, [Ca²⁺]_(i)were measured using a Fluorometric Imaging Plate Reader (FLIPR-96,Molecular Devices, Menlo Park, Calif.) as described previously (Malherbeet al., Mol. Pharmacol., 64, 823-832, 2003). Orexin A (catalog No. 1455,Toris Cookson Ltd, Bristol, UK) was used as agonist. Orexin A (50 mMstock solution in DMSO) was diluted in FLIPR buffer+0.1% BSA. The EC₅₀and EC₈₀ values of orexin-A were measured daily from standard agonistconcentration-response curves in CHO(dHFr-)-OX1R and -OX2R cell lines.All compounds were dissolved in 100% DMSO. Inhibition curves weredetermined by addition of 11 concentrations (0.0001-10 μM) of inhibitorycompounds and using EC₈₀ value of orexin-A as agonist (a concentrationwhich gave 80% of max agonist response, determined daily). Theantagonists were applied 25 min (incubation at 37° C.) before theapplication of the agonist. Responses were measured as peak increase influorescence minus basal, normalized to the maximal stimulatory effectinduced by EC₈₀ value of orexin-A or orexin-B. Inhibition curves werefitted according to the Hill equation: y=100/(1+(x/IC₅₀)^(nH)), wheren_(H)=slope factor using Excel-fit 4 software (Microsoft). K_(b) valueswere calculated according to the following equationK_(b)=IC₅₀/(1+[A]/EC₅₀) where A is the concentration of agonist addedwhich is very close to agonist EC₈₀ value, and IC₅₀ and EC50 values werederived from the antagonist inhibition and orexin-A or B agonist curves,respectively.

The compounds show a K_(b) value in human on orexin receptor as shown inthe table below.

K_(b) (μM) K_(b) (μM) K_(b) (μM) OX2R OX2R OX2R Example (human) Example(human) Example (human) 1 0.0292 12 0.214 23 0.1225 2 0.0573 13 0.149124 0.7543 3 0.2068 14 0.3038 25 0.6749 4 0.1292 15 0.0819 26 0.1777 50.0318 16 0.1473 27 0.0839 6 0.115 17 0.565 28 0.3306 7 0.0623 18 0.355229 0.4067 8 0.0829 19 0.6896 30 0.3398 9 0.3367 20 0.0772 31 0.539 100.1653 21 0.3962 32 0.1846 11 0.7255 22 0.0566

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatin capsules. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are however usually required in thecase of soft gelatin capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a method for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of formula I and/or pharmaceutically acceptable acid additionsalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

The invention also provides methods for the therapeutic and/orprophylactic treatment of sleep disorders including sleep apnea,narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythmsdisorder, restless leg syndrome, psychiatric, neurological andneurodegenerative disorders including anxiety, depression, manicdepression, obsessive compulsive disorders, affective neurosis,depressive neurosis, anxiety neurosis, mood disorder, delirium,panic-attack disorder, posttraumatic stress disorders, sexualdysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer'sand Parkinson's diseases, dementia, mental retardation, dyskinesias suchas Huntington's disease and Tourette syndrome, addictions, cravingassociated with drug abuse, seizure disorders, epilepsy, metabolicdiseases such as obesity, diabetes, eating disorders including anorexiaand bulimia, asthma, migraine, pain, neuropathic pain, sleep disordersassociated with psychiatric, neurological and neurodegenerativedisorders, neuropathic pain, enhanced or exaggerated sensitivity to painsuch as hyperalgesia, causalgia, and allodynia, acute pain, burn pain,back pain, complex regional pain syndrome I and II, arthritic pain,post-stroke pain, post-operative pain, neuralgia, pain associated withHIV infection, post-chemotherapy pain or irritable bowel syndrome, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The most preferred indications in accordance with the present inventionare those, which include sleep disorders including sleep apnea,narcolepsy, insomnia, parasomnia, jet lag syndrome, circadian rhythmsdisorder, restless leg syndrome, psychiatric, neurological andneurodegenerative disorders including anxiety, depression, manicdepression, obsessive compulsive disorders, affective neurosis,depressive neurosis, anxiety neurosis, mood disorder, delirium,panic-attack disorder, posttraumatic stress disorders, sexualdysfunction, schizophrenia, psychosis, cognitive disorders, Alzheimer'sand Parkinson's diseases, dementia, mental retardation, dyskinesias suchas Huntington's disease and Tourette syndrome, addictions, cravingassociated with drug abuse, seizure disorders, epilepsy, metabolicdiseases such as obesity, diabetes, eating disorders including anorexiaand bulimia, asthma, migraine, pain, neuropathic pain, sleep disordersassociated with psychiatric, neurological and neurodegenerativedisorders, neuropathic pain, enhanced or exaggerated sensitivity to painsuch as hyperalgesia, causalgia, and allodynia, acute pain, burn pain,back pain, complex regional pain syndrome I and II, arthritic pain,post-stroke pain, post-operative pain, neuralgia, pain associated withHIV infection, post-chemotherapy pain, irritable bowel syndrome andother diseases related to general orexin system dysfunction. Morepreferred indications are sleep disorders, particularly sleep apnea,narcolepsy, insomnia, parasomnia, jet lag syndrome and sleep disordersassociated with neurological diseases.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of a compound of general formula I or of thecorresponding amount of a pharmaceutically acceptable salt thereof. Thedaily dosage can be administered as single dose or in divided doses and,in addition, the upper limit can also be exceeded when this is found tobe indicated.

Tablet Formulation(Wet Granulation)

mg/ tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound offormula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. MagnesiumStearate 1 1 1 1 Total 167 167 167 831Manufacturing Procedure

-   1. Mix items 1, 2, 3 and 4 and granulate with purified water.-   2. Dry the granules at 50° C.-   3. Pass the granules through suitable milling equipment.-   4. Add item 5 and mix for three minutes; compress on a suitable    press.

Capsule Formulation

mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound offormula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200200 300 600Manufacturing Procedure

-   1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.-   2. Add items 4 and 5 and mix for 3 minutes.-   3. Fill into a suitable capsule.    Experimental Part:

EXAMPLE 1{3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone

a) Step 1:

3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester

A mixture of 220 mg (1.1 mmol) 3-aminomethyl-pyrrolidine-1-carboxylicacid tert-butyl ester (commercially available), 188 mg (1 mmol)2,6-dichloro-benzooxazole (commercially available) and 303 mg (3 mmol)NEt₃ in 4 mL DCM was stirred at room temperature over night. Afterevaporation to dryness the residue was purified with flash columnchromatography on silica eluting with a gradient formed from ethylacetate and heptane. The product containing fractions were evaporated toyield 351 mg (99%) of the title compound. MS (m/e): 352.4 (MH⁺).

b) Step 2:

(6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride

A mixture of 350.2 mg (0.99 mmol)3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidine-1-carboxylicacid tert-butyl ester and 3 mL 4N HCl in dioxane was stirred at roomtemperature over night. The mixture was decanted and the residueevaporated to dryness to yield the title compound which was used in theconsecutive step without further purification. MS (m/e): 252.2 (MH⁺).

c) Step 3:

{3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone

A mixture of 20 mg (0.07 mmol)(6-chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride,15 mg (0.77 mmol) 2,6-dimethoxybenzoyl chloride and 10 mg (0.1 mmol)NEt₃ in 2 mL DCM was shaken at room temperature over night. Afterevaporation the residue was subjected to purification by preparativeHPLC on reversed phase eluting with a gradient formed from acetonitrile,water and formic acid. The product containing fractions were evaporatedto yield 6.5 mg (22%) of the title compound. MS (m/e): 416.2 (MH⁺).

INTERMEDIATE 1(6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine,hydrochloride

In analogy to the procedure described for the synthesis of(6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride(example 1, step 2) the title compound was prepared from(S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and2,6-dichloro-benzooxazole (commercially available) and subsequentcleavage of the tert-butyloxy carbonyl-protecting group throughtreatment with HCl in dioxane. MS (m/e): 252.2 (MH⁺).

INTERMEDIATE 2(6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine,hydrochloride

In analogy to the procedure described for the synthesis of(6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride(example 1, step 2) the title compound was prepared from(S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and2-chloro-6-fluoro-benzothiazole (commercially available) and subsequentcleavage of the tert-butyloxy carbonyl-protecting group throughtreatment with HCl in dioxane. MS (m/e): 252.1 (MH⁺).

INTERMEDIATE 3(7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine,hydrochloride

In analogy to the procedure described for the synthesis of(6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride(example 1, step 2) the title compound was prepared from(S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and2-chloro-7-fluoro-benzooxazole (Bioorganic & Medicinal Chemistry Letters2007, 17, 4689) and subsequent cleavage of the tert-butyloxycarbonyl-protecting group through treatment with HCl in dioxane. MS(m/e): 236.1 (MH⁺).

INTERMEDIATE 4(6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine

In analogy to the procedure described for the synthesis of(6-Chloro-benzooxazol-2-yl)-pyrrolidin-3-ylmethyl-amine; hydrochloride(example 1, step 2) the title compound was prepared from(S)-3-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester and2,6-dichloro-quinoxaline (commercially available) and subsequentcleavage of the tert-butyloxy carbonyl-protecting group throughtreatment with HCl in dioxane. MS (m/e): 263.1 (MH⁺).

EXAMPLE 2{(S)-3-[(6-Chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone

A mixture of 146.3 mg (0.45 mmol)(6-chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3-ylmethyl-amine,hydrochloride (intermediate 1), 106.7 mg (0.586 mmol)2,6-dimethoxy-benzoic acid (commercially available) and 206.9 mg (0.64mmol) TBTU in 4 mL DMF and 0.3 mL DIPEA was shaken at room temperatureover night. The mixture was acidified with formic acid and subjected topurification by preparative HPLC on reversed phase eluting with agradient formed from acetonitrile, water and formic acid. The productcontaining fractions were evaporated to yield 72 mg (38%) of the titlecompound. MS (m/e): 416.2 (MH⁺).

In analogy to the procedure described for the synthesis of{(S)-3-[(6-chloro-benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)-methanone(example 2) further pyrrolidin-3-ylmethyl-amine derivatives have beensynthesized from their respective starting materials as mentioned intable 1. Table 1 comprises example 3-example 32.

TABLE 1 MW found structure systematic name starting materials MH+ 1

{3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)- methanone (6-chloro-benzooxazol-2-yl)-pyrrolidin-3- ylmethyl-amine; hydrochloride and 2,6-dimethoxybenzoyl chloride 416.2 2

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2,6-dimethoxy-phenyl)- methanone (6-chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate1), and 2,6-dimethoxy-benzoic acid 416.2 3

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-trifluoromethyl- phenyl)-methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 2- trifluoromethyl-benzoic acid (commercially available) 424.2 4

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy- phenyl)-methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 2- trifluoromethoxy- benzoic acid (commercially available) 440.2 5

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro- ethoxy)-phenyl]- methanone(6-Fluoro-benzothiazol- 2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine,hydrochloride (intermediate 2) and 2- (1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (commercially available) 472.2 6

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-2- trifluoromethyl-phenyl)- methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 5- methyl-2- trifluoromethyl-benzoic acid (commercially available)438.2 7

{(S)-3-[(6-Fluoro benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl- isoxazol-4-yl)-methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 5- methyl-4-phenyl- isoxazole-3-carboxylic acid (commerciallyavailable) 437.2 8

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)- methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 4- phenyl-isoxazole-5- carboxylic acid (commercially available)423.2 9

(2-Chloro-5-methyl- phenyl)-{(S)-3-[(6-fluoro- benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}- methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 2- chloro-5-methyl-benzoic acid (commercially available) 404.2 10

{(S)-3-[(6-Fluoro- benzothiazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl- phenyl)-methanone (6-Fluoro-benzothiazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 2)and 2- methoxy-5-methyl- benzoic acid (commercially available) 400.2 11

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl)-(2-trifluoromethyl- phenyl)-methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 2- trifluoromethyl-benzoic acid (commercially available) 424.2 12

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy- phenyl)-methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 2- trifluoromethoxy- benzoic acid (commercially available) 440.2 13

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro- ethoxy)-phenyl]- methanone(6-Chloro-benzooxazol- 2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine,hydrochloride (intermediate 1) and 2- (1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (commercially available) 472.2 14

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-2- trifluoromethyl-phenyl)- methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 5- methyl-2- trifluoromethyl-benzoic acid (commercially available)438.2 15

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl- isoxazol-4-yl)-methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 5- methyl-4-phenyl- isoxazole-3-carboxylic acid (commerciallyavailable) 437.2 16

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl)-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)- methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 5- methyl-4-phenyl- isoxazole-3-carboxylic acid (commerciallyavailable) 423.2 17

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-chloro-5-methyl- phenyl)-methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 2- chloro-5-methyl-benzoic acid (commercially available) 404.2 18

{(S)-3-[(6-Chloro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl- phenyl)-methanone (6-Chloro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 1)and 2- methoxy-5-methyl- benzoic acid (commercially available) 400.2 19

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy- phenyl)-methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 2- trifluoromethyl-benzoic acid (commercially available) 424.2 20

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro- ethoxy)-phenyl]- methanone(7-Fluoro-benzooxazol- 2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine,hydrochloride (intermediate 3) and 2- (1,1,2,2-tetrafluoro-ethoxy)-benzoic acid (commercially available) 456.2 21

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-2- trifluoromethyl-phenyl)- methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 5- methyl-2- trifluoromethyl-benzoic acid (commercially available)422.2 22

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl- isoxazol-4-yl)-methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 5- methyl-4-phenyl- isoxazole-3-carboxylic acid (commerciallyavailable) 421.2 23

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)- methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 4- phenyl-isoxazole-5- carboxylic acid (commercially available)407.2 24

(2-Chloro-5-methyl- phenyl)-{(S)-3-[(7-fluoro- benzooxazol-2-ylamino)-methyl]-pyrrolidin-1-yl}- methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 2- chloro-5-methyl-benzoic acid (commercially available) 388.2 25

{(S)-3-[(7-Fluoro- benzooxazol-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl- phenyl)-methanone (7-Fluoro-benzooxazol-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine, hydrochloride (intermediate 3)and 2- methoxy-5-methyl- benzoic acid (commercially available) 384.2 26

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy- phenyl)-methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 2-trifluoromethyl-benzoic acid (commercially available) 451.2 27

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro- ethoxy)-phenyl]- methanone(6-Chloro-quinoxalin-2- yl)-(R)-1-pyrrolidin-3- ylmethyl-amine(intermediate 4) and 2- (1,1,2,2-tetrafluoro- ethoxy)-benzoic acid(commercially available) 483.2 28

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-2- trifluoromethyl-phenyl)- methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 5- methyl-2-trifluoromethyl-benzoic acid (commercially available) 449.2 29

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl- isoxazol-4-yl)-methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 5-methyl-4-phenyl- isoxazole-3-carboxylic acid (commercially available)448.3 30

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl)-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)- methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 4-phenyl-isoxazole-5- carboxylic acid (commercially available) 434.2 31

(2-Chloro-5-methyl- phenyl)-{(S)-3-[(6-chloro- quinoxalin-2-ylamino)-methyl]-pyrrolidin-1-yl}- methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 2-chloro-5-methyl-benzoic acid (commercially available) 415.2 32

{(S)-3-[(6-Chloro- quinoxalin-2-ylamino)- methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl- phenyl)-methanone (6-Chloro-quinoxalin-2-yl)-(R)-1-pyrrolidin-3- ylmethyl-amine (intermediate 4) and 2-methoxy-5-methyl- benzoic acid (commercially available) 411.2

1. A compound of formula I

wherein R¹ is halogen; R² is halogen, lower alkyl, lower alkoxy, loweralkyl substituted by halogen, lower alkoxy substituted by halogen orphenyl; Hetaryl is

X is S; Ar is aryl or heteroaryl; n is 0, 1 or 2; and m is 0, 1 or 2; ora pharmaceutically suitable acid addition salt, optically pureenantiomer, racemate or diastereomeric mixture thereof.
 2. The compoundof claim 1, wherein R² is lower alkyl, lower alkoxy, lower alkoxysubstituted by halogen or phenyl.
 3. The compound of claim 2, wherein R²is methyl, methoxy, 1, 1, 2, 2-tetrafluoro-ethoxy or phenyl.
 4. Thecompound of claim 1, wherein R¹ is chloro or fluoro.
 5. The compound ofclaim 1, wherein n is
 1. 6. The compound of claim 1, selected from thegroup consisting of{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethyl-phenyl)-methanone;{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-trifluoromethoxy-phenyl)-methanone;{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-2-trifluoromethyl-phenyl)-methanone;{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone;(2-chloro-5-methyl-phenyl)-{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-methanone;and{(S)-3-[(6-fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(2-methoxy-5-methyl-phenyl)-methanone.7. The compound of claim 1, selected from the group consisting of{(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-[2-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-methanone;{(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-methyl-3-phenyl-isoxazol-4-yl)-methanone;and{(S)-3-[(6-Fluoro-benzothiazol-2-ylamino)-methyl]-pyrrolidin-1-yl}-(5-phenyl-isoxazol-4-yl)-methanone.
 8. A pharmaceutical composition comprising acompound of formula I

wherein R¹ is halogen; R² is halogen, lower alkyl, lower alkoxy, loweralkyl substituted by halogen, lower alkoxy substituted by halogen orphenyl; Hetaryl is

X is S; Ar is aryl or heteroaryl; n is 0, 1 or 2; and m is 0, 1 or 2; ora pharmaceutically suitable acid addition salt, optically pureenantiomer, racemate or diastereomeric mixture thereof and apharmaceutically acceptable carrier.